Safety and Pharmacokinetics of NXN-188 After Single and Multiple Doses in Five Phase I, Randomized, Double-Blind, Parallel Studies in Healthy Adult Volunteers

Background: NXN-188 is a dual-action oral therapeutic being developed for the treatment of acute migraine. The mechanism of action of NXN-188 involves inhibition of both the neuronal nitric oxide synthase enzyme isoforrn and affinity for serotonin (5-hydroxytryptarnine(1B/D)) receptors. Objectives: The aims of the initial Phase I clinical studies were to compare the pharmacokinetic (PK) properties of NXN-188 administered as a single dose or multiple twice-daily doses to healthy adult volunteers and to determine the tolerability of NXN-188 in these individuals. Methods: Healthy adult male and female subjects were enrolled in 5 Phase 1, randomized, double-blind studies, all of which (except for a fed/fasted trial) were placebo controlled. In the 4 single-dose studies, which differed with respect to feeding status and the formulation used (capsules or Solution), Subjects received NXN488 at doses of 2 to 800 mg (0.027-11.2 mg/kg). In the repeat-dose study, Subjects received 50-mg (0.71 mg/kg) doses twice daily for 4 days. Serum samples were analyzed for NXN-188 using validated HPLC-MS/MS methods. Standard clinical laboratory analyses (chemistry, hematology, and Urinalysis) and measurements of serum creatine kinase and myoglobin levels were conducted at screening, admission, discharge, and follow-up. Baseline and postexposure values were compared to assess tolerability. Electrocardiography and physical examination were conducted at screening and at discharge and follow-up if nN negat ve change occurred from the previous findings. Vital signs (heart rate, blood pressure, respiratory), including assessment for orthostatic changes, were measured at screening, check-in, and follow-up visits (: l hour before dosing, every 30 minutes for the first 4 hours, then every hour for the next 4 hours, then every 4 hours for the remainder of the 24-hour study). Adverse events were recorded, reviewed, and monitored throughout the study. Results: Two hundred three subjects (102 women, 101 men) 18 to 50 years of age were enrolled in the 5 studies; 168 subjects received NXN-188 and 35 received placebo. Most (91%) of the subjects were white; weight ranged from 69.3 to 71.8 kg (body mass index, 24.5-25.8 kg/m(2)). The initial absorption phase of orally administered NXN-188 peaked at similar to 1 hour, followed by a second absorption phase with a T-max of similar to 4 to 5 hours. Exposure (C-max and AUC) increased in a slightly greater than close-proportional manner across a dose range of 2 to 800 mg (0.027-11.2 mg/kg). Elimination was multiexponential, with an Initial rapid plasma drug elimination (plasma concentrations decreased similar to 70%-90% from C-max, within 24 hours after dosing), followed by a prolonged clearance phase of very low NXN-188 concentrations (similar to 1%-5% of C-max) that persisted for several weeks. Clearance ranged from 70 to 130 L/h, and the NXN-188 half-life ranged from 11 to 178 hours. Neither food nor gender had any measurable effect on the PK properties of NXN-188. Overall, dizziness was reported more often in the NXN-188 groups than in the placebo groups (6.3% vs 2.90%, respectively). Frequently reported adverse events that occurred more often in the placebo groups than in the NXN-188 groups were somnolence (11.4% vs 6.3%, respectively), and headache (8.6% vs 6.9%). Incidences of orthostatic hypotension (6.3% vs 5.7%) and postural (orthostatic) tachycardia syndrome (6.3% vs 5.7%) were comparable in the NXN-188 and placebo groups, respectively. No serious adverse events were reported at any dose of NXN-188 up to the Current maximum dose (800 mg or 11.2 mg/kg). Conclusion: NXN-188 exhibited linear pharmacokinetics over the dose range studied and appeared to be well tolerated in these healthy volunteers. (Clin Ther. 20-10;32:146-160) (C) 2010 Excerpta Medica Inc.